The proposed research is aimed at critically testing the prediction from Orgel's error catastrophe hypothesis, that cells accumulate mutations as exponential function of their age. The autoradiographic assay for diptheria toxin-resistance (48) will be used to measure the frequence of mutation in cultured human diploid fibroblasts. Cells will come from normal donors and from abnormal aging-related syndromes (progeria, Werner's syndrome, Cocayne's syndrome and ataxia telangiectasia). The autoradiographic assay detects toxin-resistant mutant cells independently of their capacity to divide or to synthesize DNA (the only requirement being that cells are capable of synthesizing proteins). It can thus detect mutants with equal accuracy in populations as they progress from phase I through phase III of their life. By using the autoradiographic assay, it will be possible to measure the frequency of mutation in a relatively well defined genetic system not only in actively growing cultures, or in cultures which are at the terminal stages of their proliferative life, but also in cultures where all cell proliferation has come to an end. It is precisely at these stages where the accumulation of errors is predicted by Orgel's theory to be most dramatic.